Monomer and polymer adhesives have found wide use in many applications, including industrial, consumer household, as well as medical applications. Included among these adhesives are the 1,1-disubstituted ethylene monomers and polymers, such as the alpha-cyanoacrylates. Since the discovery of the adhesive properties of such monomers and polymers, they have found wide use due to the speed with which they cure, the strength of the resulting bond formed, and their relative ease of use. These characteristics have made the alpha-cyanoacrylate adhesives the primary choice for numerous applications such as bonding plastics, rubbers, glass, metals, wood and, more recently, biological tissues.
It is known that monomeric forms of alpha-cyanoacrylates are extremely reactive, polymerizing rapidly in the presence of even minute amounts of an initiator, including moisture present in the air or on moist surfaces such as animal, including human, tissue. Once polymerization has been initiated, the cure can be very rapid. In general, these cyanoacrylates can be extremely sensitive making them challenging to work with and to store.
Medical applications of 1,1-disubstituted ethylene adhesive compositions include use as an alternative or an adjunct to surgical sutures and/or staples in wound closure, as well as for covering and protecting surface wounds such as lacerations, abrasions, burns, minor cuts or other wounds. When an adhesive is applied to surfaces to be joined, it is usually applied in its monomeric form, and the resultant polymerization gives rise to the desired adhesive bond. Additionally, these adhesives have found use as sealants, and protective coverings to immobilize microbes prior to surgery as a surgical drape, to prevent blister formation, or undesirable effects from radiation.
When such adhesive compositions, and the applicators used to apply the adhesive, are desired to be used in the medical arts, it is often required, or at least preferred, that they be sterile. It is also desirable that the composition retain a shelf life of one to two years and that the container or applicator in which it is stored does not react with or adversely affect the composition and its performance, particularly after sterilization.
A variety of sterilization methods are generally used to sterilize monomeric and polymeric compositions as well as their containers or applicators. These methods include chemical, physical, and irradiation techniques. Examples of chemical methods include exposure to ethylene oxide or hydrogen peroxide vapor. Physical methods of sterilization may include, for example, sterilization by dry or moist heat. Gamma irradiation, electron beam (e-beam) irradiation, and microwave irradiation are some common examples of irradiation methods. Aseptic filling may also be used to provide sterile compositions.
The process of gamma sterilization is extremely thorough and can be used on sealed packages, a package's contents and outer wrap all of which can be fully sterilized after assembling, requiring no post-processing cooling. Gamma sterilization's downside is that it can alter the physical properties of the component package materials and alter the adhesive contained inside. Gamma sterilization is a robust process, especially at the prescribed doses of a minimum of 25 kGy, as taught in U.S. Pat. No. 5,530,037 to McDonnell et al., and can cause premature polymerization of the monomers. In addition, many additive substances, for example polymers used as thickeners, undergo degradation resulting in unwanted contaminants or properties of the resulting substance. This significantly limits the formulator's ability to formulate adhesive compositions which have the desirable stability and flow characteristics, and which can be sterilized.
Lower dose irradiation (gamma or electron beam irradiation less than 10 kGy) is taught in U.S. Patent Application Publication No. 2007/0065334 to Shalaby. However it is used to generate gaseous formaldehyde which in turn sterilizes cyanoacrylate adhesives. The radiochemical sterilization utilized is a costly, complicated hybrid sterilization process encompassing chemical and radiation sterilization using a precisely radiolytically generated gaseous formaldehyde, in combination with a complex packaging system with specialized holders for the adhesive packages.
Other references teach using lower dose irradiation to sterilize 2-cyanoacrylate ester adhesive compositions utilizing electron beam irradiation. U.S. Patent Application Publication No. 2007/0248486 to Morales discloses sterilizing 2-cyanoacrylate ester adhesive compositions using a dose of 1 to 15 kGy and specifically state that the combination of the monomeric 2-cyanoacrylate and electron beam irradiation together have a lethal effect on microbials. And, U.S. Pat. No. 6,143,805 to Hickey et al. teaches an e-beam dosage as 5-100 kGy, preferably about 10-50 kGy, and more preferably 20-30 kGy to sterilize cyanoacrylates, with an optional post gamma irradiation step at an undisclosed dose.
U.S. Pat. No. 6,248,800 to Greff et al. discloses a method for sterilizing cyanoacrylate ester compositions at room temperature using lower irradiation doses of electron beam irradiation of preferably 15 to 20 kGy, but also includes the limitation that the average bulk density of the materials comprising the packaging elements can be no more than about 0.2 g/cm3.
U.S. Pat. No. 7,371,345 to Stewart et al. utilizes dry heat and low dose e-beam and gamma irradiation to sterilize cyanoacrylate adhesive compositions and kits but in multiple packages and steps. The components of an adhesive composition are packaged and separated from each other, or a composition is separated from other kit components, and each are individually sterilized in series and/or in parallel using any sterilization method, including e-beam and gamma, at doses (same or different) such that the cumulative dose of any component is not excessive so as to alter the components' properties. Such a method avoids the problem of some adhesive compositions not being able to be fully sterilized as a single composition, because certain of the component materials react adversely to the sterilization process.
As the use of cyanoacrylate adhesives in the medical field continues to grow, the need exists for new and improved ways to utilize readily available gamma sterilization technology to sterilize cyanoacrylate adhesives without encountering disadvantageous complicated packaging systems, expensive components or complex methods.